ABSTRACT

Context Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of
action and predictable antithrombotic effect, has the potential to be a simple
therapeutic alternative to current standard treatment of acute venous thromboembolism.

Objective To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin
treatment for the prevention of recurrent venous thromboembolism.

Design, Setting, and Patients Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in
Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute
deep vein thrombosis, of whom approximately one third had concomitant pulmonary
embolism. The study was conducted at 279 centers in 28 countries from September
2000 through December 2002.

Interventions Patients were randomized to receive 6 months of treatment with either
oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg
twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an
international normalized ratio of 2.0 to 3.0.

Results Venous thromboembolism recurred in 26 of the 1240 patients assigned
to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the
1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute
difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence
interval [CI], –1.0% to 1.3%). This met the prespecified criterion for
noninferiority. Corresponding values for major bleeding were 1.3% and 2.2%
(difference, −1.0%; 95% CI, –2.1% to 0.1%), and for mortality
were 2.3% and 3.4% (difference, –1.1%; 95% CI, –2.4% to 0.2%).
Alanine aminotransferase levels increased to more than 3 times the upper limit
of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran
and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly
asymptomatic. Retrospective analysis of locally reported adverse events showed
a higher rate of serious coronary events with ximelagatran (10/1240 patients)
compared with enoxaparin/warfarin (1/1249 patients).

Conclusions Oral ximelagatran administered in a fixed dose without coagulation monitoring,
was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis
with or without pulmonary embolism and showed similar, low rates of bleeding.
Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients
require regular monitoring; the mechanism requires further evaluation. Prospective
assessment of coronary events in future studies is warranted.

Figures in this Article

Current therapy for patients with acute venous thromboembolism consists
of 5 to 7 days of unfractionated heparin or low-molecular-weight heparin,
overlapped with and followed by long-term oral anticoagulation with a vitamin
K antagonist such as warfarin. Heparins must be given parenterally, and their
administration requires considerable health care resources. Warfarin has an
unpredictable dose response, interacts with many drugs, and can be affected
by changes in diet; thus, continued coagulation monitoring and dose adjustment
are necessary.1,2

Ximelagatran, an orally administered direct thrombin inhibitor, is rapidly
absorbed and quickly converted to its active form, melagatran, which has a
bioavailability of approximately 20%.3,4 Melagatran
is a reversible, active-site inhibitor of both free and clot-bound thrombin5 and has predictable and reproducible pharmacokinetic
and pharmacodynamic properties3,4 unaffected
by obesity, ethnic origin, food, and alcohol. Melagatran also has a low binding
affinity for plasma proteins6 and a low potential
for drug interactions.7 These factors support
the use of fixed dosing without the need for coagulation monitoring and subsequent
dose adjustment.

In studies to date, ximelagatran has been shown to be effective and
well tolerated for the prevention of venous thromboembolism after major elective
hip or knee surgery,8,9 for the
prevention of stroke and systemic embolism in patients with atrial fibrillation,10 and for the long-term secondary prevention of venous
thromboembolism.11 In addition, ximelagatran
showed promise for the effective treatment of acute deep vein thrombosis in
a phase 2 study.12 In long-term studies, ximelagatran
has been consistently associated with increased levels of liver enzymes in
some patients.10,11 We conducted
a large international, multicenter, double-blind, randomized trial (the Thrombin
Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) in patients
with acute deep vein thrombosis with or without pulmonary embolism, to compare
the efficacy and safety of oral ximelagatran with that of standard enoxaparin/warfarin
treatment.

METHODS

Study Design

The THRIVE Treatment Study was a randomized, double-blind trial that
began as 2 separate and almost identical trials, each designed to demonstrate
the noninferiority of ximelagatran relative to enoxaparin/warfarin for the
prevention of recurrent venous thromboembolism. Originally, 1 of the trials
was to have been conducted in North America and the other in countries outside
North America. However, due to a low recruitment rate in North America and
a low overall blinded event rate in countries outside North America, the executive
committees agreed to merge the trials into a single large joint study approximately
1 year after the initial commencement to deliver conclusive results in a timely
manner. A single executive committee was then formed, comprising all members
of both committees, to supervise trial conduct. No examination or unblinded
analysis of recurrence rates per treatment group was performed at any time
before completion of the merged study.

The primary objective of the THRIVE Treatment Study was to compare the
efficacy of ximelagatran (Exanta, AstraZeneca) with that of enoxaparin/warfarin
for the prevention of recurrent venous thromboembolism. Secondary objectives
were to compare safety, particularly with respect to bleeding, a combined
end point of recurrent venous thromboembolism or major bleeding, and all-cause
mortality. The study groups were ximelagatran in combination with enoxaparin
placebo/warfarin placebo or enoxaparin/warfarin in combination with ximelagatran
placebo. Oral ximelagatran, 36 mg, or placebo was given twice daily without
coagulation monitoring or dose adjustment for 6 months. Enoxaparin, 1.0 mg/kg,
or placebo was given subcutaneously twice daily for at least 5 days (maximum,
20 days) and, concomitantly, encapsulated warfarin (1.0 mg and 2.5 mg) or
placebo tablets were administered once daily and adjusted to maintain an international
normalized ratio (INR) between 2.0 and 3.0. Enoxaparin or enoxaparin placebo
was stopped after 2 consecutive INR measurements reached the target range.

Blood samples were drawn per usual clinical practice for INR measurements
to adjust warfarin (or warfarin placebo) dose, either at local laboratories
or using a point-of-care device that provided encrypted values. In either
case the results were sent to an independent study monitor who provided the
attending physicians with the actual INR (enoxaparin/warfarin group) or a
sham INR (ximelagatran group) to maintain blinding. The sham INR value was
computer-generated according to an algorithm that took into account the previous
warfarin placebo doses, sex, age, previous INR results, and phase of therapy.
The attending physician adjusted the doses of warfarin or placebo according
to the reported results (either real or sham).

Patients

Eligible patients were 18 years or older, with acute, objectively confirmed
deep vein thrombosis, with or without pulmonary embolism, for whom anticoagulant
therapy was planned for at least 6 months. The diagnosis of deep vein thrombosis
was based on a clear-cut noncompressible proximal venous segment identified
by venous ultrasonography or a persistent intraluminal filling defect in the
calf or proximal veins identified by contrast venography.

The criteria for exclusion from the study included the presence of 1
or more of the following: symptoms of deep vein thrombosis for longer than
2 weeks; contraindications to anticoagulants; weight greater than 140 kg;
clinically significant bleeding disorder; stroke within the previous 30 days;
hemodynamically unstable pulmonary embolism; platelet count less than 90 × 103/μL; calculated creatinine clearance less than 30 mL/min (0.501
mL/s); clinically significant liver disease or levels of aminotransferases
persistently increased to greater than twice the upper limit of normal; thoracic
or central nervous system surgery within the previous 2 weeks or planned major
surgery during the study; expected survival of less than 6 months; or treatment
with thrombolytic agents within 14 days before randomization. Women of childbearing
potential had to be using reliable contraception or have a negative pregnancy
test. Therapeutic doses of unfractionated or low-molecular-weight heparin
were allowed for a maximum of 24 hours before randomization. Concomitant use
of other anticoagulant or fibrinolytic agents was not allowed. Acetylsalicylic
acid, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors
were discouraged but permitted at the lowest effective dose. Other antiplatelet
drugs were not allowed.

Randomization occurred after objective confirmation of deep vein thrombosis.
Patients were randomized using an adaptive balancing algorithm that accounted
for those patients having active malignancy within the past 2 years and for
country (center in North America). Randomization was undertaken by phoning
a central number to obtain the treatment allocation for an enrolled patient.
Study medication was centrally labeled and distributed to the sites, where
it was stored according to local requirements. Baseline contralateral compression
ultrasonography and ventilation-perfusion lung scanning were performed within
72 hours of study entry to facilitate adjudication in cases of suspected recurrence.
Based on the clinical presentation and lung scan results, the clinical centers
assessed whether each patient had concomitant pulmonary embolism at presentation.
Pulmonary embolism was considered probable if the lung scan showed a high
probability (segmental or greater defect on perfusion with normal corresponding
ventilation) or if patients had symptoms suggestive of pulmonary embolism
combined with an abnormal perfusion scan, even if criteria for high probability
were not met.

Study visits were scheduled at 2, 4, 8, 12, 16, 21, and 26 weeks postrandomization.
At the 26-week visit, study treatment was stopped and a follow-up visit was
scheduled after an additional 2 weeks. Completion of treatment was defined
as last visit while taking study drug occurring after 24 weeks. Patients who
discontinued study medication prematurely were followed up for recurrent venous
thromboembolism and death until 26 weeks, whereas data on bleeding events
were only collected on-treatment, a period that included 48 hours after stopping
study drugs. In addition, patients were asked to make an emergency visit if
they developed symptoms consistent with deep vein thrombosis, pulmonary embolism,
or bleeding. At each routine visit, the patient was asked about symptoms of
recurrent venous thromboembolism, and appropriate diagnostic testing was performed
if there was a clinically suspected event. Bleeding and other clinical events
were evaluated, concomitant medication was noted, and tablets were counted
to determine adherence.

The study was performed in accordance with the Declaration of Helsinki
and good clinical practice, approved by all local medical ethics committees,
and supervised by the Joint Executive Committee. Written informed consent
was obtained from all patients.

Outcome Measures

If a suspected recurrent thromboembolic event occurred, diagnostic testing
was performed. Recurrent deep vein thrombosis was diagnosed by ultrasonography
if there was a new noncompressible venous segment in the proximal veins, an
increase of 4 mm or more in thrombus diameter with compression, or an increase
of between 1 and 4 mm in diameter combined with an extension of at least 4
cm in length. When venography was performed, a new persistent intraluminal
defect or extension of a previous defect by 4 cm or more was considered diagnostic
of recurrence. Venography was required for confirmation of suspected distal
(calf) deep vein thrombosis. In patients with suspected pulmonary embolism
during follow-up, recurrence was diagnosed if repeat lung scanning showed
a new segmental perfusion defect with normal ventilation, if computed tomography
or pulmonary angiography showed a persistent intraluminal filling defect,
or if new perfusion lung scan defects, not meeting the criteria for a high
probability of pulmonary embolism, were seen together with new objectively
confirmed deep vein thrombosis. All suspected recurrences were adjudicated
by an independent central adjudication committee that reviewed the diagnostic
testing.

Major bleeding was defined as fatal bleeding, bleeding in critical sites,
or overt bleeding with a reduction in hemoglobin of at least 2 g/dL (20 g/L)
or leading to transfusion of 2 or more units of blood or packed red cells.
Minor bleeding was defined as clinically significant bleeding that did not
meet the criteria for major bleeding. All suspected bleeding events were reported
and centrally adjudicated.

All deaths were adjudicated and classified as fatal pulmonary embolism,
fatal bleeding, or death from other causes. Monthly liver function testing
(levels of alanine aminotransferase, aspartate aminotransferase, alkaline
phosphatase, and bilirubin) was performed. The protocol was amended after
approximately 1 year, requiring weekly testing if any test result was greater
than twice the upper limit of normal; the protocol also required discontinuation
of study drug if the test results increased to greater than 5 times the upper
limit of normal or if an increase to more than 3 times the upper limit of
normal persisted during 4 weeks. An independent data and safety monitoring
board reviewed the outcome measures on a regular basis to ensure patient safety
throughout the study. A stopping rule for a negative trend with respect to
efficacy of ximelagatran vs standard therapy was to be applied, but no formal
interim analyses were performed.

Statistical Analysis

The primary analysis was based on time to objectively confirmed recurrent
venous thromboembolism, using an intention-to-treat principle. All data for
all randomized patients receiving at least 1 dose of study drug were included
up to 6 months or until premature withdrawal from study assessments; all data
for such patients were included up to the point of study withdrawal. The risk
of recurrence was also analyzed according to an on-treatment approach, in
which all data in the intention-to-treat population collected more than 48
hours after a patient permanently discontinued allocated treatment were excluded.
Patients without an event and with their last visit within 168 to 196 days
were considered event-free at day 182. The primary objective was to determine
whether treatment with ximelagatran is noninferior to the enoxaparin/warfarin
regimen, using a predefined margin for the acceptable difference.13 A priori, the noninferiority criterion was as follows:
the upper limit of a 2-sided 95% confidence interval (CI) around the absolute
difference in cumulative risk of recurrence between treatments at 6 months
should be less than 4%. Based on International Conference on Harmonisation
guidelines,14 the noninferiority margin aimed
to be less than the largest clinically acceptable difference against the comparator
and to preserve the effect of the comparator against a putative placebo comparison.
Similar noninferiority margins (3%-5%) have been used in other studies comparing
different heparin regimes in acute venous thromboembolism.15- 19 Kaplan-Meier
estimates of the cumulative risk and the corresponding variance according
to the Greenwood formula were used when calculating the CI and the corresponding P values. For bleeding, only on-treatment analyses were
performed since no data on bleeding were collected beyond 2 days after discontinuation
of study medication. Other outcomes were compared using both the intention-to-treat
and on-treatment approaches. A Cox regression model was used to explore possible
interactions between treatment and various baseline characteristics. The Fisher
exact test was used for comparison of proportions. All reported P values are 2-sided; P<.05 was considered
statistically significant. Analyses were conducted using SAS version 8.2 (SAS
Institute Inc, Cary, NC) and Proc-StatXact version 5 (Cytel Software Corp,
Cambridge, Mass).

For the North American study, which began recruiting in September 2000,
the planned sample size was 1650, based on an expected recurrence rate of
4%15- 19 and
a noninferiority margin of 4%, accepting a 2-sided type I error of 5% and
a type II error of less than 5%. For the study outside North America, which
began recruiting in October 2000, the planned sample size was 1200, based
on the same expected recurrence rate and noninferiority margin, accepting
a 2-sided type I error of 5% and a type II error of 10%. After consultation
with the study statistician, the Joint Executive Committee decided that a
revised sample size, sufficient to show at least 50 recurrent events (approximately
2500 patients) would be the target of enrollment for the merged study.

RESULTS

Study Patients

Between September 2000 and May 2002, 2528 patients were randomized at
279 centers in 28 countries. Thirty-nine patients did not receive study drug
(18 in the ximelagatran arm, 21 in the enoxaparin/warfarin arm) (Figure 1). Of the remaining 2489 patients, 1240
received ximelagatran and 1249 received enoxaparin/warfarin, representing
the intention-to-treat population. The 2 groups were similar with respect
to age, weight, sex, creatinine clearance, and risk factors for venous thromboembolism
(Table 1). Pulmonary embolism was considered
by local assessment to be present in 37% of the ximelagatran-treated and 36%
of the enoxaparin/warfarin–treated patients.

Treatment and Follow-up

At least 24 weeks of study treatment was completed (December 2002) by
76% (947/1240) and 82% (1018/1249) of patients in the ximelagatran and enoxaparin/warfarin
groups, resulting in an average exposure of 154 and 158 days, respectively
(Figure 1). The average proportion of
time within the target INR range of 2.0 to 3.0 after the initial 30 days was
75% of sham INRs in the ximelagatran group, compared with 61% in the enoxaparin/warfarin
group. Adherence was estimated by the proportion of ximelagatran/ximelagatran
placebo tablets taken (according to pill count) in relation to days from first
dose to last dose. Ninety-three percent of ximelagatran-treated patients took
more than 80% of the ximelagatran tablets and 94% of the enoxaparin/warfarin–treated
patients took more than 80% of the ximelagatran placebo tablets.

During the follow-up period, 11 patients in the ximelagatran group withdrew
consent, 10 were lost to follow-up, and 4 terminated the study follow-up for
other reasons. In the enoxaparin/warfarin group, 11 withdrew consent, 14 were
lost to follow-up, and 2 terminated the study follow-up for other reasons.

Recurrent Venous Thromboembolism

The primary efficacy end point of recurrent venous thromboembolism (intention-to-treat
analysis) occurred in 26 and 24 patients in the ximelagatran and enoxaparin/warfarin
groups, respectively, corresponding to estimated cumulative risks of 2.1%
and 2.0% (Table 2 and Figure 2). The upper limit of the 2-sided 95% CI for the difference
between the groups was 1.3%, establishing our prespecified noninferiority
criterion for ximelagatran compared with enoxaparin/warfarin. The on-treatment
analysis showed 6-month cumulative recurrence rates of 2.0% and 1.5% in the
ximelagatran and enoxaparin/warfarin groups, respectively (Table 2).

A, Time to recurrent venous thromboembolism according to intention-to-treat
analysis. Absolute difference between ximelagatran and enoxaparin/warfarin
during 6 months of treatment was 0.2% (95% confidence interval, −1.0%
to 1.3%). B, Time to major bleeding according to on-treatment analysis. Absolute
difference between ximelagatran and enoxaparin/warfarin during 6 months of
treatment was −1.0% (95% confidence interval, −2.1% to 0.1%; P = .07).

Bleeding and Mortality

The cumulative risk of major bleeding (on-treatment analysis) at 6 months
in the ximelagatran-treated patients was 1.3% compared with 2.2% for those
receiving enoxaparin/warfarin (Table 3 and Figure 2). Major or minor bleeding was comparable
in the 2 treatment groups. The locations of major bleeding in the ximelagatran
group were gastrointestinal (5), urogenital (5), intraocular (2), nasal (1),
and subarachnoidal (1); in the enoxaparin/warfarin group the locations were
gastrointestinal (11), intramuscular (4), urogenital (3), intra-articular
(2), gynecological (2), subdural (1), intracerebral (1), and unspecified location
(1).

All-cause mortality was not significantly different between the 2 groups
(intention-to-treat and on-treatment analyses) (Table 3).

Combined End Point of Recurrent Venous Thromboembolism or Major Bleeding

The time-to-event analysis suggested a greater rate of early recurrence
of venous thromboembolism in the ximelagatran group, but the maximum difference
of 0.7% at 30 days was not statistically significant (95% CI, –0.1%
to 1.6%) (Figure 2). The same analysis
of major bleeding shows an apparent increase in early events in the enoxaparin/warfarin
group, with a nonsignificant difference of 0.6% at 30 days (95% CI, –1.3%
to 0.1%) (Figure 2). The resulting cumulative
risk for the combined end point of recurrent venous thromboembolism or major
bleeding was similar over time for both groups.

Adverse Events

The incidences of alanine aminotransferase levels that increased to
greater than 3 times the upper limit of normal in the ximelagatran and enoxaparin/warfarin
groups were 9.6% (n = 119) and 2.0% (n = 25), respectively.
(In a post hoc analysis including local laboratory data collected outside
protocol specifications or posttreatment, 8 and 2 additional patients with
alanine aminotransferase levels increased to greater than 3 times the upper
limit of normal were identified in the ximelagatran and enoxaparin/warfarin
groups, for a total of 127 patients [10.2%] and 27 patients [2.2%], respectively.)
In the ximelagatran-treated patients, peak elevations of alanine aminotransferase
levels were reached after a median of 84 days (second and third quartiles,
64-116 days). Treatment was discontinued in 76 patients and continued in 43
patients. Alanine aminotransferase values normalized during follow-up in 68
of the 76 patients discontinuing and in 36 of the 43 patients continuing ximelagatran,
with a similar recovery pattern. Normalization occurred after a median of
74 days (second and third quartiles, 45-114 days). Of the remaining 15 patients,
1 died (see below), 1 had alcohol abuse as a probable explanation of enzyme
elevation, the results of 10 had returned to below twice the upper limit of
normal at the latest observation, and 3 were lost to follow-up. Of the 25
patients in the enoxaparin/warfarin group, normalization during follow-up
was documented in 23 patients but not in the remaining 2. In the ximelagatran
group, there was 1 patient with fatal outcome of hepatitis B not known at
the time of inclusion and 1 patient with suspected study drug–induced
hepatitis that resolved after discontinuation of treatment. Most of the elevations
in enzyme levels occurred without any associated clinical symptoms.

In the ximelagatran group, 2 additional fatal outcomes occurred following
investigator-reported serious hepatobiliary adverse events. One patient had
hepatorenal syndrome. The other patient had cholecystitis, which revealed
cholecystic carcinoma at surgery. In the enoxaparin/warfarin group, 2 patients
died following hepatobiliary serious adverse events: 1 with hepatitis C not
known at inclusion, the other with pancreatic carcinoma. None of these 4 cases
had alanine aminotransferase levels increased to greater than 3 times the
upper limit of normal.

Locally reported serious coronary events, with symptomatic myocardial
ischemia warranting hospitalization, were noted in 10 of 1240 ximelagatran-treated
patients compared with 1 of 1249 enoxaparin/warfarin–treated patients
(P = .006). Four of the 10 events in the
ximelagatran group were diagnosed as myocardial infarctions (1 fatal), compared
with none in the enoxaparin/warfarin group. One of the myocardial infarctions
in the ximelagatran group occurred 6 weeks after discontinuation of ximelagatran
and switching of study therapy to aspirin and open-label warfarin, during
investigation of peripheral vascular disease.

COMMENT

This study, the largest to date of anticoagulant therapy in patients
with acute deep vein thrombosis, shows that during 6 months of treatment,
oral ximelagatran, 36 mg twice daily, administered without coagulation monitoring
or dose adjustment, is as effective as enoxaparin followed by warfarin, with
a similar bleeding risk.

The overall recurrence and major bleeding rates over 6 months in our
study were somewhat lower than the rates reported over 3 months of follow-up
for similar studies (4%-5%19- 21 and
2%-3%, respectively19,21). It
is possible that the complexity of the study introduced a selection bias,
leading to the enrollment of patients with lower risks of recurrent venous
thromboembolism and bleeding. However, except for a somewhat lower proportion
of patients with cancer, a group that has higher recurrence and bleeding rates,22,23 patient characteristics are consistent
with those seen in other studies,19 and more
than one fifth of patients had previous venous thromboembolism and one third
had pulmonary embolism.

The choice of the prespecified noninferiority efficacy margin (4%) was
based on a higher expected primary event rate than what was actually observed.
However, the upper limit of the CI for the observed absolute difference in
event rate was 1.3% at 6 months, which is considered clinically acceptable
and consistent with noninferiority of ximelagatran compared with standard
treatment.

To ensure validity of results, patients and their physicians and nurses
were blinded as to study group, and an independent adjudication committee
confirmed all outcomes. Strict adjudication criteria may have contributed
to the low recurrence rate. An increase in the sample size to achieve narrower
CIs around the point estimates for recurrence and bleeding maintained internal
validity. Treatment was given for at least 6 months, consistent with common
clinical practice.

The 6-month treatment with ximelagatran was generally well tolerated
except for the development of increased levels of alanine aminotransferase
in about 10% of patients, leading to more frequent discontinuation of study
drug in the ximelagatran group. Elevated levels of alanine aminotransferase
have been observed in 6% to 13% of patients in previous studies of prolonged
ximelagatran use.10,11,24 The
mechanism is under investigation but currently is not known, and the clinical
importance of the elevation of liver enzymes remains to be fully determined.
Of 43 patients who experienced alanine aminotransferase levels increased to
more than 3 times the upper limit of normal and who continued treatment with
ximelagatran, 36 showed normalized levels during follow-up. Normalization
while continuing therapy has also been reported in other studies.10,11 It is not yet certain on the basis
of this study how frequently liver enzyme levels need to be tested. The retrospective
observation that there appeared to be significantly more acute coronary events
in ximelagatran-treated patients is unexplained. This will be explored in
further studies, with prospective evaluation and independent adjudication
of suspected events.

The results of this study were achieved using a fixed oral dose of ximelagatran,
36 mg twice daily. During the early treatment period there was an apparent
difference in recurrent venous thromboembolism favoring the enoxaparin/warfarin
group, and of major bleeding favoring the ximelagatran group; however, in
a post hoc analysis, neither of these differences was statistically significant.

In conclusion, for the initial and prolonged treatment of deep vein
thrombosis, direct thrombin inhibition with oral ximelagatran, 36 mg twice
daily, was as effective as enoxaparin/warfarin, without the need for coagulation
monitoring or dose adjustment. The mechanism and clinical importance of the
increased liver enzyme levels in ximelagatran-treated patients requires further
evaluation. Prospective assessment of coronary events in future studies is
warranted.

Financial Disclosures: Drs Fiessinger, Huisman,
and Bounameaux have served as consultants for AstraZeneca. Dr Davidson has
been a clinical investigator in anticoagulant research with AstraZeneca, Sanofi,
Organon, Aventis, and Bristol-Myers Squibb, and has served as a consultant
or occasional speaker (sometimes for honoraria) for each of these sponsors.
Dr Francis has served as a consultant for AstraZeneca. Dr Eriksson has served
as a consultant for AstraZeneca. Dr Ginsberg has received funding from AstraZeneca
for consultation on ximelagatran or as unencumbered educational or research
grants.

Funding/Support: This study was funded by AstraZeneca.

Role of the Sponsor: The Joint Executive Committee
was entirely responsible for the design, conduct, and analyses of the study.
The committee had nonsponsor co-chairmen and a majority of nonsponsor voting
members. Four members of the committee were from the sponsor (Dr Lundström,
Dr Berkowitz [medical input to trial design, conduct, and interpretation],
Mr Nyström [statistical input to trial design, data analysis, and interpretation],
and Ms Tedroff [collection, management, and analysis of study data]). The
sponsor, AstraZeneca, held the data and performed the data analyses under
the direction of the Joint Executive Committee. This committee had full and
free access to all primary data and had full independence in deciding what
to publish. Dr Lundström, Dr Berkowitz, Mr Nyström, and Ms Thorsén
were involved in the preparation, review, and approval of the manuscript.

Independent Statistical Analysis: Dr Hans Wedel
(Professor of Epidemiology and Biostatistics, Nordic School of Public Health,
Gothenburg, Sweden) performed an independent statistical review of the study
and validated methodology, primary and secondary analyses performed, and results
obtained.

International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use. ICH Guidelines. Available at: http://www.ich.org. Accessibility verified
January 12, 2005

A, Time to recurrent venous thromboembolism according to intention-to-treat
analysis. Absolute difference between ximelagatran and enoxaparin/warfarin
during 6 months of treatment was 0.2% (95% confidence interval, −1.0%
to 1.3%). B, Time to major bleeding according to on-treatment analysis. Absolute
difference between ximelagatran and enoxaparin/warfarin during 6 months of
treatment was −1.0% (95% confidence interval, −2.1% to 0.1%; P = .07).

International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use. ICH Guidelines. Available at: http://www.ich.org. Accessibility verified
January 12, 2005

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